Whereas 17β-estradiol (E2) is protective in experimental models of myocardial and brain ischemia, its effect on skin ischemia remains unknown. Here, we assessed the protective effect of E2 in a mouse model of skin ischemia, mimicking the surgery of skin flaps. Whereas necrosis appeared in the half portion of the skin flap within one week after surgery in ovariectomized mice, it was reduced up to 10-fold when mice were pre-treated with E2, at least 3 days before the surgery. The beneficial effect of E2 appeared to be due to an increase in skin survival, revealed by measuring viability of ex vivo explants and enhancement of the anti-apoptotic Bcl-2 protein expression in vivo. This protective effect on the skin contributes to the protection of the vascular network and facilitates reperfusion which is found to be accelerated in ovariectomized E2-treated mice, while hemorrhages were observed in untreated mice. E2 also increased expression of FGF-2 isoforms in the skin and circulating VEGF in the serum. Finally, this protective effect of E2 was abolished in estrogen receptor deficient mice (ER⍺-/-) but maintained in chimeric mice reconstitued with ER⍺-deficient bone marrow, indicating dispensable action of E2 in bone-marrow derived cells. This protective effect of E2 was mimicked by treatment with tamoxifen, a selective estrogen receptor modulator (SERM).

In conclusion, we demonstrated for the first time that E2 exerts a major preventive effect of skin flap necrosis through a prevention of ischemic-induced skin lesions, including those of the vascular network, which contributes to accelerate the reperfusion of the skin flap.